Capsule and film-forming composition comprising gum arabic

ABSTRACT

A capsule for oral delivery of a composition comprises 60% to 95% by weight of gum arabic and to the remainder a water-soluble polymer, a hydrocolloid and a plasticizer. The proportion of gum arabic is preferably 70% to 90% by weight of all components. The water-soluble polymer is preferably a hydroxypropylmethylcellulose or carboxymethylcellulose or alginetes. The hydrocolloid is preferably a carrageenan or agar gum or galactomannan or a mixture thereof. The capsule may be is containing medicinal or pharmaceutical agents as fill material. The capsule has good mechanical strength and low brittleness. The presence of gum arabic in a solution raises the solubility of other film-forming polymers.

FIELD OF THE INVENTION

The present invention relates to capsules for oral delivery, whichcontain medicinal, pharmaceutical or other agents as fill materials.Concurrently, the invention relates to compositions used for preparationof such capsules.

BACKGROUND OF THE INVENTION

Soft capsules are widely used in the food and pharmaceutical industriesfor encapsulating vitamins, medications, cosmetics, paint, pigment andother substances in the form of emulsions or oil solutions. Theapplications of soft capsules have markedly increased due to the growingconsumption of products in a convenient, encapsulated form.

Hard capsules are generally used in medicine as containers formedications, allowing their successive delivery into the digestivesystem. Shell formation is typically accomplished by immersing shapingpins in an aqueous solution of gelatine containing the requiredingredients, and heating the solution. Hard capsules used for the oraldelivery of medications should have the ability to dissolve in aqueousmedia. They may also be required to disintegrate under the influence ofintestinal media over a required period.

Gelatine is commonly used for preparing both soft and hard capsules.Gelatine can be obtained from pig and cow by-products such as bones,skins and white connective tissue, and has good mechanical andprocessing properties. In spite of the wide application of gelatinecapsules in medicine, large groups of people are not able to ingestthem, for ethnic or religious reasons. In addition, recently observedcross-species contamination from cattle with bovine spongiformencephalopathy (BSE) to humans has had a negative impact on the use ofgelatine capsules.

As an alternative to gelatine-based capsules, capsules for medical usecan be made from various water-soluble synthetic polymers, capable offorming strong and elastic films. For example, WO 97/35537 A1International Application Publication discloses the use of polyvinylalcohol, polyethylene oxide and polycaprolactone in soft-shell capsulepreparation. This is achieved by elastically deforming two films to adesired shape, followed by filling and sealing the film about thefilling material. However, the process requires the films to be solvatedwith appropriate solvent prior to encapsulation to cause partialsolvation of the material surface, such that surface can adhere to andseal the film material.

WO 00/27367 A1 International Publication discloses the use ofwater-soluble cellulose derivatives as film-forming materials for softcapsule shell preparation. One such material ishydroxypropylmethylcellulose (HPMC). In this case, capsules generallycomprise a film 18 to 200 μm in width, laminated on one side withnatural gums such as carrageenan, gum arabic or soya bean proteins. Anintermediate adhesive layer is applied between the two layers. However,these capsules are brittle, and the films lose their originaltransparency. This has been attributed to the use of low molecularweight HPMC.

WO 98/27151 A1 International Publication describes soft capsulesproduced using water-soluble cellulose ethers in combination withhydrocolloids and cross-linking agents. Cellulose ethers with alkyl orhydroxyalkyl pendant groups, such as methyl, hydroxyethyl, hydroxypropyland hydroxyethylmethylcellulose can be used. The preferred celluloseether is HPMC, which is recommended as a basic material (up to 95%) incomposition for soft capsules, is used in the form of 2% solutions.Other components include hydrocolloids, plasticizers and sequesteringagents. However, the use of HPMC as a basic film-forming material islimited due to low solubility of this substance in water; a large amountof water is required in the film production process.

U.S. Pat. No. 6,214,376 B1 patent, which is the most similar to thepresent invention, discloses the compositions for soft and hard capsulesfor oral delivery, as well as the composition of capsules themselves.The water solution of composition according to U.S. Pat. No. 6,214,376B1 comprising a plasticizer, kappa-carrageenan, and at least onenon-termoreversible gum is selected from group consisting of hydrolyzedstarches, dexrins, proteins, polyviniylpyrrolidone and gum arabic. Thoseadditional materials may be present at levels from 0% to about 25% ormore of the composition.

At the same time the carrageenan comprises at least 50% by weight of allfilm-forming material in the above composition. The carrageenantherefore may be present as 75% or 50% by weight of all gums incomposition. However, carrageenan, like other hydrocolloids, is notcapable of forming highly concentrated solutions and thus has little usein this technology.

Chemically-modified natural materials can be used for the preparation ofhard gelatine-free capsules. Capsules comprising water-soluble celluloseethers or cellulose ethers with polyvinyl acetate have been proposed.Shape-forming is achieved by immersing pins of the appropriate size intoan aqueous solution, followed by drying. However, the use of thesematerials causes slipping of the capsules from the pins and theformation of a wrinkled surface. Another disadvantage of capsules madefrom cellulose ethers is their tendency to form cracks during removalfrom the pins. Processing also requires additional heating of the pinsmaking the use of standard equipment impossible.

The various conventional gelatine-free capsules described above, mayalso be contaminated with harmful chemical reagents. This isparticularly undesirable for capsules for use in medicine or the foodindustry.

Gum arabic is produced by natural exudation of the acacia tree (AcaciaSenegal). It is a brittle, tough solid material comprising a mixture ofamber-coloured, partially transparent pieces of various size and shape.Gum arabic is a natural bio-polymer with a molecular weight up to9.0-10⁵ g/mol and a polysaccharide chemical structure comprising about13% of carboxyl groups, 0.3% of nitrogen and 4% of inorganic salts. Thechemical structure of the polysaccharide fraction is complicated andincludes residues of galactose, arabinose, rhamnose and glucuronic acidin amounts of 45÷46%, 23→24%, 13÷14% and 14÷16%, respectively, with theratio of 3/2/1/1. This material is relatively cheap compared to othernatural gums and does not contain tannins. Studies have shown thatcasting gum arabic from an aqueous solution produces films of lowmechanical strength and extreme brittleness and thus the material hasnot been used as a major component in capsule preparations.

SUMMARY OF THE INVENTION

The present invention is based on the surprising discovery that thepresence of gum arabic in a solution raises the solubility of otherfilm-forming polymers. Thus, it has been discovered that a solution ofgum arabic and other film-forming polymers can be used to produce softand hard capsules of high mechanical strength and improved flexibility.

According to the main aspect of the invention, a capsule comprises 60%to 95% by weight gum arabic and to the remainder a water-solublepolymer, a hydrocolloid and a plasticizer. The proportion of gum arabicis preferably 70% to 90% by weight. These capsules may be containingmedicinal or pharmaceutical agents as fill material.

The water-soluble polymer is preferably alginetes or cellulose ether(e.g. alkyl- and/or hydroxyalkyl-substituted cellulose ether) orhydroxypropylmethylcellulose or carboxymethylcellulose. The hydrocolloidis preferable a carrageenan (kappa-carrageenan) or agar gum orgalactomannan or a mixture thereof.

The plasticizer is preferable 1, 2-propylene glycol or glycerol orglycerol triacetate or glucose or sorbitol or sucrose or fructose ormaltose or cellobiose or lactose or CaCl₂.7H₂O or triethyl citrate ortributyl citrate or dioctyl sodium sulfosuccinate or polyethylene glycolor carbamide or a mixture thereof

According to the other main aspect of the invention, a film-formingcomposition for oral delivery capsules comprising in an aqueous solution60% to 95% by all film-forming components weight of gum arabic and tothe remainder a water-soluble polymer, a hydrocolloid and a plasticizer.

A capsule of the invention may be used in drug delivery as having goodmechanical strength and low brittleness. At the same time the capsule ofthe invention comprises an inexpensive major component and therefore canbe mass-produced.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention are further explained through description of the preferredembodiments of accomplishment and applied drawing containing the FIG. 1which is a graph illustrating the kinetic of water absorption fromsaturated vapor phase at 24° C. by various film-forming materials: GumArabic—the Curve 1; hydroxypropilmethyl cellulose—the Curve 2; sodiumalginete—the Curve 3; kappa-karageenan—the Curve 4.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

A capsule of the invention comprises at least 60% by weight of gumarabic. It appears that the high proportion of gum arabic that can beused in the invention may be caused by the decrease in the rate of waterabsorption at high ambient humidity, compared to the values for certainother components that can be used in the invention. Thus, thewater-absorption kinetics (at 24° C.) of gum arabic (Curve 1 accordingto FIG. 1), hydroxypropylmethyl cellulose (Curve 2), sodium alginete(Curve 3) and kappa-carrageenan (Curve 4) are shown in FIG. 1.

A film-forming composition for oral delivery capsules comprise in anaqueous solution 60% to 95% by all film-forming components dry weight ofgum arabic and to the remainder a water-soluble polymer, a hydrocolloidand a plasticizer. The proportion of gum arabic is preferably 70% to 90%by weight of all film-forming components dry weight in an aqueoussolution.

The water-soluble polymer is cellulose ether, for example alkyl- and/orhydroxyalkyl-substituted cellulose ether, or ahydroxypropylmethylcellulose or carboxymethylcellulose or alginetes. Thehydrocolloid includes a carrageenan (kappa-carrageenan) or agar gum orgalactomannan or a mixture thereof.

The plasticizer is preferable 1, 2-propylene glycol or glycerol orglycerol triacetate or glucose or sorbitol or sucrose or fructose ormaltose or cellobiose or lactose or CaCl₂.7H₂O or triethyl citrate ortributyl citrate or dioctyl sodium sulfosuccinate or polyethylene glycolor carbamide or a mixture thereof

The solubilities of HPMC, CMC and kappa-carrageenan in water at 20° C.are respectively 2, 0.5 and 0.5 g/100 ml. It will be evident fromExamples 11 to 16 that higher solubilities (respectively 5.8% HPMC, 6.5%CMC, 15% CMC, 8% HPMC, 13.2% CMC and 9.2% kappa-carrageenan) areobserved, in the presence of gum arabic.

Capsules of the invention may be prepared by dissolving gum arabic,preferably in deionised water, to obtain a solution of 1% to 40% byweight gum arabic, dissolving various polymeric components (e.g. starch,polyvinyl alcohol, hydroxypropylmethyl cellulose, carboxymethylcellulose, carrageenan, alginetes, chitosan etc.) in the solution to adesired concentration, and further dissolving a desired amount of any ofplasticizers, sequestering agents and/or mono- or divalent metal salts.The final concentration of polymeric components in solution may be inthe range of 1% to 40% by weight.

Films prepared by casting the aqueous solution on to a smooth surfaceshowed a tensile strength value of 50 to 70 kg/cm² and an elongation atbreak of 120% to 280%. These results demonstrate the applicability ofthose materials for soft capsule preparation.

Hard capsule shells may be prepared by conventional method, e.g. byimmersing shaping pins into the aqueous solution and forming shellsaround the pins. Mechanical testing of those materials prepared on thebasis of gum arabic showed tensile strength values of more than 300kg/cm² and reasonable rigidity, acceptable for hard capsule shells.Suitable water-soluble cellulose ethers include alkyl- and/orhydroxyalkyl-substituted cellulose ethers, in which there are preferablyof 1 to 4 carbon atoms in the alkyl chains. Preferred compounds includemethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,hydroxyethylmethylcellulose and hydroxyethylethylcellulose.Hydroxypropylmethylcellulose (HPMC) is particularly preferred. Theamount of cellulose ether or a mixture thereof may be 1% to 35% byweight, preferably 5% to 25% by weight.

The water-soluble polymer may alternatively be a polysaccharidecontaining carboxyl groups. Suitable such polymers include carboxymethylcellulose (CMC), carboxymethyl starch and alginetes of alkaline metals,e.g. Li⁺, Na⁺, K⁺ (from seaweeds). These may be used for agastro-resistant capsule preparation. The amount of carboxylicpolysaccharide derivative or a mixture thereof is preferably from 5% to25% by weight.

Suitable water-soluble synthetic polymers include polyvinyl alcohol,partially hydrolysed polyvinyl acetate, polyvinylpyrrolidone,polyethylene oxide, polypropylene oxide, polyacrylic and polymethacrylicacid, polyacryl amide, halide salts of quaternised polyvinyl pyridine,poly-N, N-dialkyldiallylammonium halides, and similar hydrophilicpolymers. Preferred polymers include polyvinyl alcohol, polyethyleneoxide and polyacryl amide. The amount of this polymer component ispreferably from 1% to 30% by weight.

Suitable water-soluble polysaccharides include starch, dextrins, pectinsand chitosan. The preferred polysaccharides include sucrose, starch,alginetes and chitosan. The preferred amount of this component is 0.5%to 30% by weight. Suitable hydrocolloids include gellan gum,carrageenan, agar gum (from seaweed), guar gum, xanthan, galactomannan,funoran, acetan and wellan. Such gums may provide a synergistic effectunder the mixing. The preferred gums for this purpose are carrageenan (amixture of ammonium, magnesium and sodium salts of galactose and 3,6-anhydrogalactose esters), gellan gum, mannan gum (galactomannangum/glucomannan gum) and agar. The preferred amount is 0.1% to 10% byweight.

The novel composition includes also a plasticizer such as 1,2-propyleneglycol, glycerol, mono-, di- or triacetates of glycerol, sorbitol,sucrose, fructose, maltose, cellobiose, lactose, triethyl citrate,tributyl citrate, dioctyl sodium sulfosuccinate, polyethylene glycols orthe like as well as mixtures thereof The amount is preferably from 2% to40% by weight.

Suitable sequestering agents are ethylenediaminetetraacetic acid (EDTA),boric acid, citric acid, gluconic acid, lactic acid, tartaric acid,phosphoric acid or salts thereof, lecitin, dihydroxyethylglycine andcombinations thereof. The preferred amount is preferably 0.01% to 3% byweight, and more preferably 0.1% to 2% by weight.

Monovalent or divalent cations, such as Li⁺, Na⁺, K⁺, NH₄ ⁺, Ca²⁺ orMg²⁺ may be used to adjust the extent of sequestering. Such cations willtypically be provided in the form of salts.

Capsules of the invention may comprise inert substances such as carbonblack, titanium oxide or gypsum. Flavourings, aromatic agents and/orantioxidants may be added as necessary or desired, in order to providedesired mechanical and other properties. A capsule of the invention mayalso comprise a pharmaceutically or food-acceptable colouring agent, ofwhich suitable examples are riboflavin, carotenes, chlorophyllin,indigocarmin, anthocyanines, caramel and betanin.

The following Examples illustrate the invention. In each Example, theamounts of components are given in percentage by weight.

Examples 1 to 10 illustrate the preparation of soft capsules. Theprocedure comprised dissolving gum arabic in deionised water, typicallyat room temperature, to obtain a solution containing 1% to 40% by weightof gum arabic (Solution 1). Other polymeric components such as starch,polyvinyl alcohol, HPMC, CMC, carrageenan, alginetes, chitosan, etc.were then dissolved in the Solution 1, typically at room temperature, toobtain a solution (Solution 2) having the required concentration ofvarious components. Plasticizers, sequestering agents and mono- ordivalent metal salts were then dissolved, typically at room temperature,in the Solution 2. The final concentration of polymeric components inthe solution may be in the range of 1% to 40% by weight.

Examples 11 to 17 illustrate the preparation of hard capsules. Thesewere prepared by conventional methods, involving immersing shaping pinsinto the aqueous solution and forming shells around the pins.

EXAMPLE 1

A composition of 77% gum arabic, 15.3% glycerol, 3.85% CaCl₂.7H₂O and3.85% carbamide was cast as an aqueous solution comprising 40% gumarabic, to produce an elastic film having a tensile strength of 61kg/cm² and an elongation at break of 150%.

EXAMPLE 2

A composition of 70% gum arabic, 20% glycerol, 7% dextrins and 3% starchwas cast as an aqueous solution comprising 30% gum arabic, to produce anelastic film having a tensile strength of 51 kg/cm² and an elongation atbreak of 180%.

EXAMPLE 3

A composition of 68% gum arabic, 15.8% glycerol, 10% NaCl, 5% glucoseand 1.2% polyvinyl alcohol was cast as an aqueous solution comprising30% gum arabic, to produce an elastic film having a tensile strength of65 kg/cm² and an elongation at break of 160%.

EXAMPLE 4

A composition of 75% gum arabic, 19.3% glycerol diacetate, 4.1%CaCl₂.7H₂O and 1.6% kappa-carrageenan was cast as an aqueous solutioncomprising 40% gum arabic, to produce an elastic film having a tensilestrength of 72 kg/cm² and an elongation at break of 120%.

EXAMPLE 5

A composition of 70% gum arabic, 17% glycerol monoacetate, 8% sorbitoland 5% HPMC was cast as an aqueous solution comprising 35% gum arabic,to produce an elastic film having a tensile strength of 68 kg/cm² and anelongation at break of 170%.

EXAMPLE 6

A composition of 75% gum arabic, 15% 1,2-propylene glycol, 5%carboxymethyl cellulose and 5% CaCl₂.7H₂O was cast as an aqueoussolution comprising 36% gum arabic, to produce an elastic film having atensile strength of 55 kg/cm² and an elongation at break of 200%.

EXAMPLE 7

A composition of 71% gum arabic, 18% glycerol, 5% sorbitol, 5% sodiumalginete and 1% kappa-carrageenan was cast as an aqueous solutioncomprising 32% gum arabic, to produce an elastic film having a tensilestrength of 70 kg/cm² and an elongation at break of 120%.

EXAMPLE 8

A composition of 68.5% gum arabic, 20% glycerol, 5% chitosan, 5%carbamide, 0.5% kappa-carrageenan and 1% NaCl was cast as an aqueoussolution comprising 40% gum arabic, to produce an elastic film having atensile strength of 60 kg/cm² and an elongation at break of 130%.

EXAMPLE 9

A composition of 80% gum arabic, 14% glycerol diacetate, 0.5%kappa-carrageenan, 5% HPMC and 0.5% CaCl₂.7H₂O was cast as an aqueoussolution comprising 40% gum arabic, to produce an elastic film having atensile strength of 61 kg/cm² and an elongation at break of 155%.

EXAMPLE 10

A composition of 73% gum arabic, 20% dioctyl sodium sulfosuccinate, 5%sorbitol, 1% kappa-carrageenan and 1% EDTA was cast as an aqueoussolution comprising 40% gum arabic, to produce an elastic film having atensile strength of 70 kg/cm² and an elongation at break of 255%.

EXAMPLE 11

A composition of 70% gum arabic, 12% glycerol, 3% sucrose, 13.5% HPMCand 1.5% kappa-carrageenan was cast into an aqueous solution comprising30% gum arabic, to produce an elastic film having a tensile strength of280 kg/cm² and an elongation at break of 12%.

EXAMPLE 12

A composition of 70% gum arabic, 10% glycerol monoacetate, 4% sucrose,13% CMC, 2.5% kappa-carrageenan and 0.5% CaCl₂.7H₂O was cast as anaqueous solution comprising 35% gum arabic, to produce an elastic filmhaving a tensile strength of 300 kg/cm² and an elongation at break of8%.

EXAMPLE 13

A composition of 61% gum arabic, 6.5% glycerol diacetate, 30% CMC, 2%kappa-carrageenan and 0.5% CaCl₂.7H₂O was cast as an aqueous solutioncomprising 30% gum arabic, to produce an elastic film having a tensilestrength of 400 kg/cm² and an elongation at break of 3%.

EXAMPLE 14

A composition of 63% gum arabic, 10% glycerol monoacetate, 5% sorbitol,20% HPMC, 1% kappa-carrageenan and 1% EDTA was cast as an aqueoussolution comprising 25% gum arabic, to produce an elastic film having atensile strength of 510 kg/cm² and an elongation at break of 4%.

EXAMPLE 15

A composition of 65% gum arabic, 24.5% carboxymethyl cellulose (CMC),10% glycerol and 0.5% sorbitol was cast as an aqueous solutioncomprising 35% gum arabic, to produce an elastic film having a tensilestrength of 310 kg/cm² and an elongation at break of 5%.

EXAMPLE 16

A composition of 65% of gum arabic, 20% of kappa-carrageenan, 10% ofglycerol monoacetate, 1.5% of citric acid, 0.1% of KCl and 3.4% ofsorbitol was cast as an aqueous solution comprising 30% gum arabic, toproduce an elastic film having a tensile strength of 410 kg/cm² and anelongation at break of 4%.

EXAMPLE 17

A composition of 70% gum arabic, 20% sodium alginete, 5% dioctyl sodiumsulfosuccinate, 0.5% kappa-carrageenan, 4% sorbitol and 0.5% EDTA wascast as an aqueous solution comprising 35% gum arabic, to produce anelastic film having a tensile strength of 390 kg/cm² and an elongationat break of 6%.

INDUSTRIAL APPLICATION

A capsule of the invention may be used in drug delivery. As well ashaving good mechanical strength and low brittleness, a capsule of theinvention comprises an inexpensive major component and can be massproduced. Capsules of the invention have a wide range of applications inthe food industry, pharmaceutical industry and in the applied medicine.

1. A capsule for oral delivery of a composition comprising 60% to 95% byweight of gum arabic and to the remainder a water-soluble polymer, ahydrocolloid and a plasticizer.
 2. The capsule according to claim 1,which comprises 70% to 90% by weight of gum arabic.
 3. The capsuleaccording to claim 1, wherein the water-soluble polymer is celluloseether.
 4. The capsule according to claim 1, wherein the water-solublepolymer is an alkyl- and/or hydroxyalkyl-substituted cellulose ether. 5.The capsule according to claim 1, wherein the water-soluble polymer is ahydroxypropylmethylcellulose or carboxymethylcellulose or alginetes. 6.The capsule according to claim 1, wherein the hydrocolloid is acarrageenan or agar gum or galactomannan or a mixture thereof.
 7. Thecapsule according to claim 1, wherein the hydrocolloid is akappa-carrageenan.
 8. The capsule according to claim 1, wherein theplasticizer is 1, 2-propylene glycol or glycerol or glycerol triacetateor glucose or sorbitol or sucrose or fructose or maltose or cellobioseor lactose or CaCl₂.7H₂O or triethyl citrate or tributyl citrate ordioctyl sodium sulfosuccinate or polyethylene glycol or carbamide or amixture thereof.
 9. The capsule according to claim 1, containingmedicinal or pharmaceutical agents as fill material.
 10. A film-formingcomposition for oral delivery capsules comprising in an aqueous solution60% to 95% by all film-forming components dry weight of gum arabic andto the remainder a water-soluble polymer, a hydrocolloid and aplasticizer.
 11. The composition according to claim 10, which comprises70 to 90% by all film-forming components dry weight of gum arabic. 12.The composition according to claim 10, wherein the water-soluble polymeris cellulose ether.
 13. The composition according to claim 10, whereinthe water-soluble polymer is an alkyl- and/or hydroxyalkyl-substitutedcellulose ether.
 14. The composition according to claim 10, wherein thewater-soluble polymer is a hydroxypropylmethylcellulose orcarboxymethylcellulose or alginetes.
 15. The composition according toclaim 10, wherein the hydrocolloid is a carrageenan or agar gum orgalactomannan or a mixture thereof.
 16. The composition according toclaim 10, wherein the hydrocolloid is a kappa-carrageenan.
 17. Thecomposition according to claim 10, wherein the plasticizer is1,2-propylene glycol or glycerol or glycerol triacetate or glucose orsorbitol or sucrose or fructose or maltose or cellobiose or lactose orCaCl₂.7H₂O or triethyl citrate or tributyl citrate or dioctyl sodiumsulfosuccinate or polyethylene glycol or carbamide or a mixture thereof.